Association of Time to Therapeutic Calcineurin Inhibitor (CNI) Levels to Biopsy-Proven Acute Rejection (BPAR) after Heart Transplantation

Abstract

Purpose The optimal timing for CNI initiation in patients receiving rabbit anti-thymocyte globulin (rATG) induction in heart transplant has not been established. This study explored the association of time to therapeutic CNI levels and outcomes in order to evaluate the safety and efficacy of an early versus delayed strategy in this patient population. Methods This single-center, observational, retrospective review included 83 adult patients who underwent heart transplantation between January 2012 - October 2017 and received induction therapy with rATG at the time of transplant. Patients were stratified into four groups by time to therapeutic CNI levels post-transplant: ≤ 7 days (Group 1), 8 - 30 days (Group 2), 31 - 60 days (Group 3), and > 60 days (Group 4). Patients who did not receive a CNI as maintenance immunosuppression during initial hospitalization, or received a multi-organ transplant, alemtuzumab or basiliximab as part of induction therapy, a CNI minimization strategy using everolimus or sirolimus , or no induction therapy were excluded. The primary objective was freedom from BPAR at 1, 3, 6 and 12 months. Secondary objectives included time to first rejection; renal function via serum creatinine (SCr) pre-transplant, pre- and post-CNI initiation, and at discharge; and one-year survival. Results BPAR rates at 12 months were statistically lower in Groups 1 and 4 at 25% and 13%, respectively (p = 0.02). Time to first rejection and SCr were not significantly different, however, trended towards an increase in SCr post-CNI initiation (1.3 mg/dL) in Group 1. One-year survival favored Groups 2 and 3 at 93% and 100%, respectively (p = 0.12). Risk of infection was highest in Group 1 (79%, p = 0.005). Conclusion While a strategy of early time to therapeutic CNI levels had an associated risk of renal injury and infection , delayed time to therapeutic CNI levels (> 30 days post-transplant) was not associated with an increased risk of BPAR.